Process for preparing chloroalkyl thiazoles,pyrimidines and pyridines



US. Cl. 260-251 Claims ABSTRACT OF THE DISCLOSURE Chloroalkyl thiazoles, pyridines and pyrimidines are obtained by chlorinating the corresponding alkyl thiazole, pyridine and pyrimidine in a strongly acidic medium and in the presence of a free radical initiating catalyst.

This is a continuation-in-part of application Ser. Nos. 269,862 and 293,149 filed Apr. *2, 1963, and July 5, 1963, respectively, now abandoned.

This invention relates to methods of halogenating alkyl groups in organic compounds. More particularly, it is concerned with methods of chlorinating alkyl groups at tached to the nucleus of a basic heteracyclic compound. Still more precisely, the invention relates to methods of preparing mono-, diand trichloroalkyl thiazoles, pyrimidines and pyridines from the respective alkylthiazoles, alkylpyrimidines and alkylpyridines to the substantial exclusion of nuclear halogenation. It is also concerned with processes for chlorinating chloroalkylthiazoles, chloroalkylpyrimidines, and chloroalkylpyridines having less than three chlorine atoms on an alkyl group. It is concerned still further with the preparation of novel chlorinated alkyl heterocycles.

From the large amount of scientific literature concerned with the halogenation of alkyl groups, it is known that the success with which such radicals can be halogenated depends to a large extent on the nature of the rest of the molecule. It is possible in many cases to halogenate alkyl groups by standard literature techniques. In many cases, however, this cannot be done at all, or it cannot be done without at the same time halogenating other portions of the molecule.

Among those types of alkyl group which heretofore have been very resistant to halogenation by known methods are those wherein the alkyl radical is attached directly to the nucleus of a basic five-membered heterocyclic compound such as a thiazole. Thus, there has been no feasible method known heretofore to selectively convert an alkyl thiazole to the corresponding haloalkyl thiazole. Where such halogenation is known to occur at all, it is accompanied by a substantial amount of simultaneous nuclear halogenation which, in most instances, is undesirable and to be avoided.

The alkylpyridines are one class of compounds which tend to be extremely difficult to alkyl-halogenate. In fact, recent literature (Houben-Weyl, Methoden der Organischen Chemie, 4th edition, volume V/4, p. 341 (1960); volume V/3, p. 748 (1962)) suggest that the methyl group of 3-methylpyridine cannot be halogenated at all. Rather than side-chain halogenation, the prior art indicates halogenation of the alkylpyridines to be effected by and large on the ring or nucleus.

One object of the present invention is to provide a method for chlorinating the loweralkyl substituent of loweralkyl thiazoles, loweralkyl pyrimidine and loweralkyl pyridines. Another object is provision of a method which permits such chlorination to the substantial exclusion of ring chlorination. A further object is provision of a process wherein alkylated thiazoles, pyrimidines and pyridines are converted to the corresponding mono-, dior trichlorinated reaction products. A still further object is provision of a process for chlorinating chloroloweralkyl thiazoles, pyrimidines and pyridines having less than three chloro groups on an alkyl substituent. Another object is provision of novel chlorinated alkyl heterocycles. Other objects will be apparent from the following discussion of the invention.

In accordance with this invention, it has now been found that loweralkyl thiazoles, loweralkyl pyrimidines and loweralkpl pyridines may be converted in high yield to the corresponding chloroalkyl compounds by treatment with chlorine in a reaction mixture that comprises sulfuric acid, fuming sulfuric acid (H SO SO chlorosulfonic acid or pyrosulfuric acid (H S O or mixtures of such acids. When a loweralkyl thiazole, loweralkyl pyrimidine or loweralkyl pyridine is treated with chlorine under the reaction conditions discussed hereinbelow, it has been found that chloroalkyl thiazoles, chloroalkyl pyrimidines or chloroalkyl pyridines are produced in good yields which are in many cases greater than The desired chloroalkyl thiazole, chloroalkyl pyrimidine or chloroalkyl pyridine is obtained as the predominant or major reaction product, with only a minimal amount of ring chlorination occurring. Using appropriate reaction conditions, the amount of dichloroalkyl or trichloroalkyl reaction product obtained in proportion to monochloroalkyl product can be increased. In any event, however, only minimal nuclear ring chlorination takes place.

The processes of this invention comprise carrying out the chlorination in a highly acidic reaction medium in the presence of a suitable catalyst. As the acid there may be employed chlorosulfonic acid, sulfuric acid, sulfuric acid containing sulfur trioxide, which latter mixture is generally referred to in the art as fuming sulfuric acid or oleum, pyrosulfuric (H S O or mixtures thereof. The amount of acid is critical only to the extent that there should be present at least 1 mole of acid per mole of compound to be chlorinated. In normal practice, the acid is also employed as a solvent so that the required molar relationship of acid to loweralkyl thiazole or loweralkyl pyridine is exceeded without difiiculty. With respect to the acid, for the sake of uniformity these molar ratio are expressed in terms of sulfuric acid equivalents since with other specific acids the absolute ratio will vary slightly. Thus, when chlorosulfonic acid is employed, the mole ratio of chlorosulfonic acid to loweralkyl thiazole, loweralkyl pyrimidine or loweralkyl pyridine is preferably from about 1.2-1.8:1. There should be present at least 1 mole of sulfuric acid equivalent per mole of compound to be chlorinated, and the preferred minimum amount of acid is about 1.5 moles of sulfuric acid equivalent per mole of base. A molar ratio of up to about 2.5:1 is quite satisfactory when a monochlorinated compound is desired as the predominant reaction product. When, however, predominantly dior trichlorinated product is sought, it is preferred that a ratio of acid to base of from about 2.54:l be used. Increasing the amount of acid is beneficial when diand trichloro compounds are desired because the acid serves to suppress the unwanted ring chlorination, with the result that more rigorous reaction conditions such as stronger catalysts and longer reaction periods may be used. Under such conditions diand trichlorination increases but it will be appreciated by those skilled in this art that in many cases substantial amounts of both the mono-, diand trichloroalkyl thiazoles are produced. Although it is not desired to be bound by any theoretical explanation of the role played by these acids, it is believed that a sulfate or sulfonate salt of the loweralkyl thiazole, loweralkyl pyrimidine or loweralkyl pyridine compounds 3 is formed in the reaction mixture and that in this salt form these compounds are resistant to nuclear halogenation.

The desired halogenation is preferably effected by treating the alkyl pyridine, alkyl pyrimidine or alkyl thiazoleacid reaction mixture with chlorine in the presence of a free radical initiating catalyst. According to a preferred aspect of the invention, chlorine gas i passed into the reaction mixture under conditions where atomic chlorine is produced in situ in the mixture. Conversion of chlorine gas to atomic chlorine is conveniently accomplished by exposing the reaction mass to a suitable light source such as ultraviolet, blue or fluorescent light. Alternatively, X-rays, short radio waves, micro waves or chemical free radical initiators may be employed. The preferred chemical catalysts are those known in the art as organic azo type free radical initiator catalysts. These are aliphatic azo compounds which decompose to give free radicals in solution at elevated temperatures. They are generally tertiary-alkyl-bis-azo-nitriles or carboalkoxy compounds or amides. Examples of such catalysts are a,a'-aZO-blS-iSO- butyronitrile, dimethyl-a,a-azo-bis-isobutyrate, a,a'-aZO bis-methylbutyronitrile, dihexyl-a,dazo-bis-isobutyrate, a,a'-azo-bis-isobutyramide, a,a-azo-bis-cyclopro ylpro pionitrile, a,a-azo-bis-isobutylmethylvaleronitrile and a,a-azo-bis-methylcapronitrile and the like. When the chemical free radical initiators are employed they are used in catalytic amounts and are conveniently added to the reaction mixture While chlorine gas is being passed into it.

Although it is not essential for the success of the process, a preferred embodiment of the invention comprises carrying out the chlorination in the presence of a minor amount of a halogenide of a member of Group Va of the Periodic Table of Elements having an atomic number in the range of 15-51. The elements in this group are phosphorus, arsenic and antimony and the triand penta-halogenides of these elements are suitable. Representative eX- amples are phosphorus trichloride, arsenic trichloride, antimony tribromide, phosphorus pentachloride and arsenic pentachloride. The presence of these halogenides appears to minimize chlorination of the heterocyclic nucleus, particularly when the molar ratio of acid to organic base is less than about 2:1. When larger amounts of sulfuric, fuming sulfuric, pyrosulfuric or chlorosulfonic acids are used, the nuclear halogenation is largely suppressed without the halogenide. It is preferred that about 05-10% of halogenide by weight of heterocycle be employed although larger quantities are not harmful and may, if desired, be used without adverse effect.

The time and temperature conditions of the process of this invention are, to some extent, interdependent. Neither of these factors is unduly critical to the success of the process. It is preferred to carry out the chlorination at temperatures in the range of 50150 C. when a chemical catalyst is used although reaction temperatures ranging from about room temperature up to about 200 C. may generally be utilized if desired. The reaction proceeds somewhat faster as temperature is increased and under the preferred operating conditions the monochlorination of the alkyl groups is generally substantially complete within 6 hours. Somewhat longer reaction times, e.g. 814 hours, are preferred when predominantly dior trichlorination is sought. Conversely, shorter times discourage dior trichlorination. Optimum reaction times will, of course, also depend on the particular catalyst being used, because the chloroloweralkylation reaction proceeds faster with the organic azo-bis type of chemical catalyst than it does with a light catalyst. The absolute reaction times preferred for mono-, di-, and trichlorination must, therefore, be considered in terms of the other reaction conditions.

It will be seen that by the processes of this invention, it is now possible to prepare heterocycles of the formula RCX from compounds of the formula RCHX where R is thiazolyl, pyrimidinyl, or pyridyl and each X and X is hydrogen or chloro, at least one X being chloro. The alkylated thiazoles, pyrimidines, or pyridines which are treated in accordance with this invention are loweralkyl thiazoles, loweralkyl pyrimidines or loweralkyl pyridines having 1-6 carbon atoms in the alkyl radical, such radical being methyl, ethyl, propyl, butyl and isobutyl and the like. The position of the loweralkyl group in the heterocyclic ring is not critical. As earlier mentioned, chloroalkyl thiazoles, pyrimidines and pyridines may also be chlorinated by the processes of this invention. It will be appreciated that the reaction conditions generally applicable in preparing the diand trichloralkyl heterocycles discussed hereinabove may be utilized in halogenating these chloroalkyl compounds.

Examples of the alkylated and chloroalkylated thiazoles, pyrimidines and pyridines which may 'be halogenated to the corresponding mono-, diand trichloralkyl compounds are 2-methylthiazole, 4-methylthiazole, 5- chloromethylthiazole, 2,4 dimethylthiazole, 2 ethylthiazole, 4 propylthiazole, 3 methylpyridine, 2,6 dimethylpyridine, 2 methylpyridine, 4 methylpyridine, 2,4 dimethylpyridine, 2,5 dimethlpyridine, 2 methl- 5-ethylpyridine, 2,4,6 trimethylpyridine, 2,4 diethylpyridine, 4 chloromethylpyridine, 2 dichloromethylpyridine, 4 methylpyrimidine, 2 methylpyrimidine, 5- chloromethlpyrimidine, 2 propylpyrimidine, 4 ethylpyrimidine, 4 chloromethylpyrimidine, 2 chloromethylpyrimidine, 6-ethylpyrimidine, and the like. When the alkyl group contains more than one carbon atom, halogenation occurs predominantly at the alpha carbon under the preferred reaction conditions.

The chloroalkyl thiazoles produced according to the foregoing processes are useful and important for a number of purposes. The presence of the halogen atom in the alkyl group permits hydrolysis of the monohaloalkylthiazole to the corresponding carbinol and oxidation, if desired, of the carbinol to the carboxylic acid which may in turn be esterified or reacted to form other derivatives such as amides, aldehydes and acid halides. The chloroalkyl thiazoles may be converted to the corresponding thiazole aldehyde. The chloromethyl thiazoles are thus of significant importance in that they are key intermediates in the synthesis of 2-(thiazolyl)-ben2imidazoles, which latter substances are highly active anthelmintic agents. The chloroalkyl pyridines prepared by the processes of this invention find uses for a number of purposes. 2,6-'bis-chloromethylpyridine may be converted to the 2,6- bis-hydroxymethylpyridine which finds use as a reactant in the preparation of polyurethanes. 3-hydroxymethylpyridine, which may be prepared by saponification from 3-chloromethylpyridine, finds use as a vasodilator. Nicotinic acid may also be prepared from compounds obtained by the processes of the invention. The chloroalkyl pyrimidines prepared by the processes of this invention are useful as intermediates in the preparation of organic compounds such as hydroxyalkyl pyrimidines, primidine aldehydes and carboxy pyrimidines which compounds are also intermediates in the synthesis of useful organic chemicals.

The following examples are given for the purpose of illustration and not by way of limitation:

Example 1 20 g. of 4-methylthiazole is dissolved in a mixture of 13.8 g. of 96% sulfuric acid and 14.4 g. of concentrated sulfuric acid containing 20% sulfur trioxide. 0.6 g. of phosphorus thichloride and 0.05 g. of benzoyl peroxide are then added and the mixture stirred in a quartz flask at 84 C. for 28 hours While the flask is irradiated with a quartz lamp. During this time a stream of chlorine is continuously introduced into the reaction mixture.

The mixture is then cooled and quenched by pouring over crushed ice. The quenched mixture is brought to pH 8 by the addition of solid sodium bicarbonate and then extracted with 3x 100 ml. of ether. The ether extracts are dried over magnesium sulfate and then evaporated to dryness in vacuo to give an oil which contains 44% of 4-methylthiazole and 46% of 4-chloromethylthiazole by gas chromatography analysis. The 4-chloromethylthiazole is readily identified via its hexatmine salt: 2.7 g. of the oil obtained above is added to 1.4 g. of hexamine in ml. of chloroform. The hexarnine salt which crystallizes on standing is recovered and dried.

When this experiment is carried out without addition of benzoyl peroxide to the reaction mixture, similar results are obtained.

The gas chromatography analyses referred to in this and succeeding examples are carried out using the known techniques, (eg as described in the text Gas Chromatography by A. I. M. Keulemans, Reinhold Publishing Corp., New York, N.Y., 1957) in a column whose dimensions are 2500 x 8 mm., at 70 C., using DC 200 on Chromosorb W as adsorbent, and a helium flow of about 85 on a Kromatog gas chromatography unit.

Example 2 198 g. of 4-methylthiazole and 6.3 g. of phosphorus trichloride are added to a mixture of 140 g. of fuming sulfuric acid (containing 20% S0 and 140 g. of 96% sulfuric acid. During the addition the acid mixture is cooled in ice. A stream of chlorine gas is then passed through the mixture, while vigorously stirring, for 4 hours. Concurrentlly, a solution of 4 g. of a,a'-azo-bis-isobutyronitrile in 92 g. of 96% sulfuric acid is added dropwise to the mixture. The reaction temperature is held at 85-90 C. At the end of 4 hours the mixture is poured onto 800 g. of crushed ice. An aliquot of the quenched mixture is made basic with concentrated aqueous ammonium hydroxide, then the resulting oil extracted into benzene. The benzene extract is dried over magnesium sulfate and concentrated to dryness. Analysis of the residue by gas chromatography shows that the benzene extract contains 156 g. of 4-chloromethylthiazole and 73 g. of 4-methylthiazole. The product is recovered by vacuum distillation. It distills at 50-5l C./1 mm.

Example 3 297.4 g. (3 moles) of 4-methylthiazole is added with stirring and external cooling to 237 ml. (3.6 moles) of chlorosulfonic acid. 9.4 g. of phosphorus trichloride is then added and chlorine gas passed into the reaction mixture over a period of 2 /2 hours. Concurrently, a solution of 6 g. of a,u-azo-bis-isobutyronitrile in 75 ml. of 99% sulfuric acid is added to the mixture. During this addition and that of the chlorine gas, the reaction mixture is stirred vigorously and the temperature maintained between 80- 90 C. At the end of 2 /2 hours, excess chlorosulfonic acid is removed from the clear yellow solution by distillation and the solution then poured onto 1500 g. of crushed ice. The resulting mixture is neutralized to pH 6.5 with concentrated aqueous ammonium hydroxide and kept cold by the addition of ice. The oil which separates is extracted with ,5 300 m1. of ether and the ether extracts combined, dried over magnesium sulfate and then evaporated to dryness in vacuo. The residue is distilled under vacuum to give 334 g. of 4-chloromethylthiazole, Bl. 51-52 C./1 mm. The forerun contains 26 g. of 4-methylthiazole.

When this process is carried out employing 4-ethylthiazole as starting material, 4-(OL-ChlOTOBlLhYD-fl1l320l6 is produced.

Example 4 99 g. of 4-methylthiazole is added to a mixture of 70.5 g. of fuming sulfuric acid, containing 20% S0 and 68.5 g. of concentrated sulfuric acid. 3.06 g. of phosphorus trichloride and 0.25 g. of benzoyl peroxide are then added and the mixture irradiated with a fluorescent lamp for 17 hours at 81 C. while chlorine gas is continuously passed through the mixture. The irradiation and chlorine addition is carried out in a quartz flask with vigorous stirring. The resulting homogeneous yellow product is quenched by pouring onto 300 g. of crushed ice. The resulting mixture is extracted with 2X 50 ml. of benzene and the water layer then adjusted to pH 7 with about 230 ml. of concentrated ammonium hydroxide. The resulting mixture is extracted with 3 X 100 ml. of ether and the ether extracts combined and concentrated to dryness to give a residue containing 77 g. of 4-chloromethylthiazole and 26 g. of unreacted 4-methylthiazole.

Example 5 To a solution of 50 g. of 4-methylthiazole in 176 g. of chlorosulfonic acid there is added 2.7 g. of phosphorus pentachloride and 0.125 g. of benzoyl peroxide. The resulting mixture is chlorinated for 21 hours at 78 C. while irradiating it with a fluorescent lamp. The resulting 4-chloromethylthiazo1e is recovered by the procedure of Example 4.

Example 6 12.32 g. of 2-methylthiazole is added to a mixture of 4.65 ml. of 20% oleum and 7.75 ml. of concentrated sulfuric acid; 0.25 ml. of phosphorus trichloride is added. The mixture is heated to 8090 C. and a stream of chlorine gas passed through it while 0.75 g. of a,oc'aZ0- bis-butyronitrile added in 10 increments over a period of 6 hours. The reaction mixture is then quenched by adding it to ice, and alkalized by addition of concentrated amtmonia. To mixture is extracted with an equal volume of ether, the ether extract dried over MgSO and the ether removed by distillation. The residue is distilled in vacuo. 2-chloromethylthiazole distills at 65-70 C./2 mm.

Example 7 99 g. of 4-mehylthiazole is added to a mixture of g. of 20% oleum and 92 g. of 96% sulfuric acid. 3.2 g. of phosphorus trichloride is then added. To the resulting mixture a solution of 3 g. of a,ot-azo-bis-isobutyronitrile in 72 g. of 96% sulfuric acid is added over a period of 12 hours. Over the same 12 hour period a stream of chlorine gas is passed into the mixture which mixture is vigorously stirred at a temperature of 8590 C. At the end of this time the entire mixture is poured onto 300 g. of ice and the resulting quenched mixture extracted with 3 300 ml. portions of benzene. The benzene extracts are combined, washed with dilute aqueous sodium bicarbonate and with water, and finally dried over magnesium sulfate. The benzene solution is then filtered and concentrated to dryness in vacuo. The residue is distilled at pressure of 1 mm. 4-dichloromethylthiazole distills at a temperature of 6365 C. 75 g. of product are collected. The material is recrystallized from ether-petroleum ether to give substantially pure material, M.P. 5052 C.

The benzene-extracted aqueous solution contains about 60 g. of monochloromethylthiazole.

When the above process is carried out and 4-chloromethylthiazole is used in place of 4-methylthiazole there is again obtained 4-dichloromethylthiazole.

Example 8 3.2 g. of phosphorus trichloride is added to a mixture of 99 g. of 4-methylthiazole and 152 g. of chlorosulfonic acid. To this mixture a solution of 8 g. of OL,OL'-21ZO-blS- isobutyronitrile in g. of 96% sulfuric acid is added over a period of 9 hours, with vigorous stirring. During this time a stream of chlorine gas is added to the reaction mixture at a rate of 0.4 mol per hour. During the chlorine addition the temperature of the reaction mixture is maintained at 85-90 C. At the end of the 9 hour period the mixture is added to 300 g. of ice and then extracted with 3 300 ml. portions of benzene. The benzene extracts are combind, washed with water and with sodium bicarbonate solution and dried over magnesium sulfate. The drying agent is then removed by filtration and the benzene solution distilled in vacuo. The residue remaining after removal of the benzene is distilled under 1 mm. pressure. 80 g. of 4-dichloromethylthiazole distills at 60-65 C. The product is further purified by dissolving in ether and crystallizing by the addition of petroleum ether. The pure dichlorornethylthiazole thus obtained melts at 5051 C.

68 g. of 4-chloromethylthiazole are recovered from the benzene-extracted Water layer by making this aqueous solution basic with concentrated ammonium hydroxide and extracting with benzene. The benzene extracts are concentrated to dryness and 4-monochloromethylthiazole recovered by distillation at 5152 C./1 mm.

2-dichloromethylthiazole is obtained in similar fashion from Z-methylthiazole.

When the above process is carried out and 2-(ot-chloroethyl)-thiazole is used in place of 4-methylthiazole, 2- (a,a-dichloroethyl)-thiazole is obtained.

Example 9 15 g. of 4-chloromethylthiazole is dissolved in 31 ml. of glacial acetic acid. 23 g. of freshly fused potassium acetate is added and the mixture refluxed for 2 hours. 150 ml. of water is then added, the mixture extracted with 3 X 50 ml. of ether and the combined extracts washed with saturated sodium bicarbonate solution, with water and dried over magnesium sulfate. The ether is distilled off and the residue fractionated in vacuo to give 5.5 g. of 4-acetoxymethylthiazole, B.P. 115 C./14 mm. It is saponified in the following way: It is added to a mixture of 2.98 g. of potassium hydroxide in 24 ml. of ethanol, stirred at room temperature for 4 hours and left standing for 2 days at room temperature. The ethanol is distilled off at a low bath temperature in vacuo. The residue is dissolved in a minimum volume of Water and the resulting solution extracted with 3 x 30 ml. of ether. The ether extracts are dried over magnesium sulfate, the ether distilled off and the residue fractionated in vacuo. 1.66 g. of 4-hydroxymethylthiazole is obtained, B.P. 115117 C./1l mm.

0.7 g. of 4-hydroxymethylthiazole is dissolved in 8.3 ml. of 0.1 N sulfuric acid. A solution of 1.16 g. of potassium dichrornate in 4.4 ml. of water and 1.47 ml. of sulfuric acid is added thereto with stirring over a 2-hour period. The mixture is cooled in an ice bath during the addition of the oxidizing agent. It is then held at room temperature for 15 hours and then made basic with ml. of concentrated ammonium hydroxide. The resulting mixture is filtered and the filtrate adjusted to pH 2.5 N hydrochloric acid. 8 ml. of glacial acetic acid is added and finally a solution of 2.1 g. of copper acid in 30 ml. of water is added to the acidic solution. The blue copper salt of thiazole carboxylic acid separates and is recovered by filtration. It is decomposed by adding it to ml. of 0.66 N hydrochloric acid and passing hydrogen sulfide gas through the resulting mixture. The solid copper sulfide is removed by filtration and the filtrate evaporated to dryness in vacuo, the residue dissolved in water and the pH adjusted to 2.0 with 2.5 N sodium hydroxide. The resulting mixture is cooled in an ice bath to crystallize thiazole-4-carboxylic acid. The resulting acid is recovered by filtration, washed with Water and air dried. It is converted to the acid chloride by treatment with thionyl chloride in xylene.

1.3 g. of 4-thiazolyl acid chloride and 1.3 g. of o-nitroaniline are stirred together in 3.5 ml. of pyridine at room temperature for about 12 hours. At the end of this time, the mixture is quenched in ice water and the solid nitroanilide recovered by filtration and Washer with dilute sodium carbonate solution. The solid is suspended in 15 ml. of glacial acetic acid, and 8 ml. of 6-N-hydrochloric acid added to the suspension. 6 g. of zinc dust is added in small portions to the acetic mixture. After the zinc addition is complete, and the reaction is essentially finished (by visual observation), the reaction mixture is filtered and the filtrate neutralized with concentrated ammonium hydroxide to precipitate 2-(4-thiazolyl)-benzimidazole. The product is purified by recrystallization from ethyl acetate.

The 2-chloromethylthiazole and the S-chloromethylthiazole are converted in similar fashion to 2-(2'-thiazolyl)-benzimidazole and 2-(5-thiazolyl) -ben.'zimidazole. The 2-thiazolylbenzimidazoles produced in this fashion are highly active anthelmintic agents.

Example 10 A solution of 3.36 g. of 4-dichloromethylthiazole in 50 m1. of 10% sulfuric acid is refluxed under nitrogen at a temperature of 125 to 130 C. for 2 hours under a nitrogen atmosphere. The mixture is then cooled to room temperature and 10% sodium hydroxide solution is added until the pH of the solution reaches 6. The mixture is then extracted with 3X 30 ml. of chloroform. The chloroform is next washed with water, dried over magnesium sulfate and evacuated to dryness in vacuo. 1.91 g. of 4-thiazolyl aldehyde, M.P. 6567 C. is obtained, corresponding to a yield of Thiazole-Z-aldehyde is obtained by applying the above process to 2-dichloromethylthiazole.

These thiazole aldehydes may be converted to 2-(4- thiazolyl)-benzimidazole and 2-(2-thiazolyl)-benzimidazole according to the procedures of U.S. Patent No. 3,017,415.

The above-described conversion of dihalomethylthiazole to thiazole aldehyde is being claimed in my copending application Ser. No. 142,000.

Example 11 46.5 g. (0.5 mol) of 3-methylpyridine is added to a mixture of 49 g. (0.5 mol) of 99% sulfuric acid and 50.5 g. of 20% fuming sulfuric acid. 1.6 g. of PO1 is added. While stirring at 125 C. a solution of 2 g. of azo-bis-isobutyronitrile and 46 g. of concentrated sulfuric acid is added over a 3-hour period during which time chlorine gas is introduced. The weight increase of the reaction mixture indicates an uptake of about 12 g. of chlorine. After degassing in vacuo the reaction mixture is quenched on ice, neutralized with 10% ammonia, and extracted with ether. After drying over magnesium sulfate, the ether extract is evaporated at room temperature in vacuo to give about 60 g. of a light-colored oil which is unstable at room temperature. Proton magnetic resonance data show the substance to be substantially pure 3-chloromethylpyridine containing only small amounts of starting material and 3-dichl0romethylpyridine. The picrate prepared from the product melts at l30l31 C. (lit. M.P. 133 C.). Infra red spectrographic analysis compares favorably with an authentic sample.

When the above process is carried out using 3-ethylpyridine as a reactant, 3-(a-chloroethyD-pyridine is produced.

When the above process is employed using 4-methylpyridine in place of 3-methylpyridine, 4-chloromethylpyridine is obtained.

Example 12 46.5 g. of 3-methylpyridine (0.5 mol) is dissolved in 37.2 ml. of 100% sulfuric acid. While vigorously stirring the mixture, a stream of chlorine gas is passed through at 100 C. for 3 hours during which period a solution of 2 g. of azo-bis-butyronitrile in 50 ml. of 100% sulfuric acid is added. The reaction mixture is quenched on ice. Gas chromatographic analysis shows a 1:1 ratio mixture of 3-chloromethylpyridine and 3-dichloromethylpyridine.

Example 13 214 g. (0.2 mol) of 2,6-dimethylpyridine is added slowly to 276 g. of 99% sulfuric acid. With stirring, and at a temperature of -110 C., a stream of chlorine gas and simultaneously a solution of 18 g. of azo-bis-isobutyronitrile in 300 ml. of concentrated H SO is added to the reaction mixture over a period of 12 hours. Gas chromatographic analysis shows the formation of a :3 ratio mixture of 2,6-bis-chloromethylpyridine and 2-chloromethyl-6-methylpyridine, respectively. The reaction mixture is quenched on ice, the pH raised to pH 8 by addition of 10% ammonia, filtered, extracted with ether, the extracts washed with water, dried over MgSO; and fractionated at 3 mm. pressure. The fraction boiling between 7090 C. consists mainly of 2-chloromethyl-6-methylpyridine whereas the fraction boiling between 95-1 10 C. consists mainly of 2,6-bis-chloromethylpyridine. On cooling the second fraction, crystallization occurs. After recrystallizing from an ethanolzwater mixture (3:1), 2,6- bis-chloromethylpyridine (M.P. 7273 C.) results. The hydrochloride made from the first fraction melts at 152 C.

35 gms. of 2,6-bis-chloromethylpyridine (0.1 mol) is refluxed with a mixture of 19 g. of concentrated HCl and 300 ml. of water for 22 hours. Upon saturation with solid K CO crystals of 2,6-bis-hydroxymethylpyridine form. These crystals are then filtered out, dissolved in 250 ml. of hot ethanol, the solution mixed with charcoal and filtered and concentrated in vacuo. The addition of 16 gm. of benzene causes separation of crude 2,6-bis-hydroxymethylpyridine. On recrystallization from a benzenemethanol mixture (20:1) pure 2,6-bis-hydroxymethylpyridine results (M.P. 115 C.).

Example 14 46.5 g. of 3-methylpyridine (0.5 mol) is dissolved with ice cooling in a mixture of 49 g. of 98% sulfuric acid and 50.3 g. of 20% oleum. This mixture is irradiated in a quartz flask with an ultraviolet lamp for 48 hours at 70-75" C. while under vigorous stirring, a stream of chlorine gas is passed through it. A clear solution of 3-trichloromethylpyridine results. After quenching on ice and adjusting the pH with concentrated NH OH to pH 8, the reaction mixture is left standing overnight, filtered, the filtrate extracted with ether, and the pH of the water phase adjusted to 2.53 by the addition of HCl. After cooling to 10 C., the nicotinic acid formed separates in crystalline form. It is filtered, washed with an etheralcohol mixture, and dried. A high yield of pure nicotinic acid is obtained, M.P. 224227 C.

When 4-chloromethylpyridine or 2-(a-chloroethyl)- pyridine is used in place of 3-methylpyridine in the abOve process, the haloalkylpyridine product obtained is 4-trichloromethylpyridine or 2- (a,a,u-trichloroethyl)-pyridine, respectively.

Example 15 8.5 gms. of Z-methylpyrimidine is dissolved in 30 g. of concentrated sulfuric acid. Chlorine gas is then introduced over a period of 2 hours while the mixture is agitated and irradiated with ultraviolet light. The temperature is maintained between 60 C. and 70 C. Then the reaction mixture is degassed in vacuo, quenched on ice, and neutralized by the addition of dilute ammonia. The resulting 2-chloromethylpyrimidine is isolated by ex traction with methyl ether.

When 4-methylpyrimidine or S-methylpyrimidine is used in the above process instead of Z-methylpyrimidine, there is obtained 4-chloromethylpyrimidine or 5-chloromethylpyrimidine, respectively.

Example 16 4.2 grns. of S-methylpyrimidine is dissolved in a mixture of 8 g. of 98% sulfuric acid and 8 g. of 20% oleum. Under vigorous stirring, chlorine gas is passed through the mixture at 5060 C. for 12 hours, while it is irradiated by an ultraviolet lamp. The reaction mixture is then degassed, quenched on ice and neutralized by the addition of dilute ammonia. The 5-di-chloromethylpyrimidine produced is extracted with ethyl acetate. The solution formed is then dried over magnesium sulfate and the solvent is evaporated in vacuo.

When the above process is carried out and 2-chloromethylpyrimidine, 6-methylpyrimidine or 4-ethylpyrimidine is used in place of S-methylpyrimidine, there is obtained 2-dichloromethylpyrimidine, 6-dichloromethylpyrimidine, or 4-(a,a-dichloroethyl)-pyrimidine, respectively.

Example 17 To a mixture of 55 g. of 98% sulfuric acid and 57 g. of oleum (20%) is added 44 g. of 2-methylpyrimidine. The mixture is vigorously stirred and chlorine gas is passed through it at 110 C. for 8 hours during which period 4 g. of azo-bis-butyronitrile in 100% sulfuric acid is added. The reaction mixture is then quenched on ice water and the pH adjusted to pH 7 by the addition of concentrated ammonium hydroxide. The product, 2-trichloromethylpyrimidine is separated by extraction with diethyl ether.

When S-methylpyrimidine or 6-methylpyrimidine is used in place of Z-methylpyrimidine in the above process, there is obtained 5-trichloromethylpyrimidine or 6- trichloromethylpyrimidine, respectively.

What is claimed is:

1. The process for preparing a compound of the formula which comprises intimately contacting a heterocyclic compound of the formula where R is a member selected from the group consisting of thiazolyl, pyrimidyl and pyridyl and each X and X is selected from the group consisting of hydrogen and chlorine, at least one X being chlorine, with chlorine in the presence of a free radical initiating catalyst in a reaction medium comprising a member of the group consisting of sulfuric acid, fuming sulfuric acid, chlorosulfonic acid, and pyrosulfuric acid said medium containing at least one mole of acid per mole of heterocyclic compound.

2. The process of claim 1 wherein 4-chloromethyl thiazole is obtained by chlorination of 4-methyl thiazole.

3. The process of claim 1 wherein the reaction mixture contains a minor amount of a halogenide of a member of the Group 5a of the Periodic Table of Elements having an atomic number of from 15 to 51.

4. The process for preparing chloromethyl thiazole, chloromethyl pyridine or chloromethyl pyrimidine that comprises treating methyl thiazole, methyl pyridine or methyl pyrimidine with chlorine in a reaction medium comprising sulfuric acid, fuming sulfuric acid, chlorosulfonic acid or pyrosulfuric acid, said medium containing at least one mole of acid per mole of heterocyclic compound and containing a minor amount of an organic aliphatic azo-type catalyst.

5. The process of claim 4 wherein 4-chloromethyl thiazole is obtained by chlorination of 4-methyl thiazole.

6. The process for making dichloromethyl thiazole that comprises treating methyl thiazole with chlorine in the presence of a free radical initiating catalyst and in a reaction medium comprising sulfuric acid, fuming sulfuric acid, chlorosulfonic acid or pyrosulfuric acid, wherein the molar ratio of sulfuric acid equivalent to methyl thiazole is at least 2.5: 1, and continuing said chlorine treatments until the quantity of dichloromethyl thiazole in the reaction mixture exceeds the quantity of monochloromethyl thiazole.

7. The process of claim 6 wherein 4-dichloromethyl thiazole is obtained from 4-methyl thiazole.

8. The process of claim 7 wherein the catalyst is an organic aliphatic azo-type catalyst.

9. The process for preparing a chloroalkyl thiazole, chloroalkyl pyridine or chloroalkyl pyrimidine that comprises treating a loweralkyl thiazole, loweralkyl pyridine or loweralkyl pyrimidine having from 1 to 6 carbon atoms in the alkyl radical with chlorine in the presence of a free radical initiating catalyst in a reaction medium 11 12 comprising sulfuric acid, fuming sulfuric acid, chloro- References Cited sulfonic or pyrosulfuric acid, said medium containing at Chemical Abstracts VOL 51 16436-16438 (1957).

least one mole of acid per mole of heterocyclic com- ALEX MAZEL, Primary Examiner 10. A compound of the group consisting of mono- 5 chloroloweralkyl pyrimidine, Z-dichloroloweralkyl py- RUSH Asslstant Exammel' rimidinc, S-dichloroloweralkyl pyrimidine, Z-trichloroloweralkyl pyrimidine and 5-trichloroloweralky1 pyrimi- CL dine. 204-158; 260-77, 290, 302, 999 

